Pramlintide Acetate Safety Review Dragos Roman MD Center for Drug Evaluation and Research.

Pramlintide AcetateSafety Review

Dragos Roman MD

Center for Drug Evaluation and ResearchCenter for Drug Evaluation and Research

Pramlintide Acetate Safety Review Outline

• Phase 3 Trials

– Motor vehicle accident (MVA)-related events

• Serious adverse events (SAEs) associated with hypoglycemia (type 1 diabetes)

– Other accident/injury-related events

• Assisted hypoglycemia


• Phase 3 Trials





Phase 3 Clinical Trials

• Long-term controlled studies in patients with type 1 diabetes:– 137-121 1 year

– 137-112 1 year

– 137-117 6 months

• Long-term controlled studies in patients with type 2 diabetes:– 137-122 1 year

– 137-123 6 months

– 137-111 1 year

Phase 3 Clinical Trials (Type 1 Diabetes)

Pramlintide Placebo

Total Population 1179 538

Completed Trial 781 (66%) 403 (75%)

Withdrew(all reasons)

398 (34%) 135 (25%)

Withdrew(adverse events)

214 (18%) 31 (6%)

First Month Nausea-Related Withdrawals -Type 1 Diabetes

0

1

2

3

4

5

6

7

137-121 137-117 137-112 All studies

PramlintidePlacebo

% withdrawals

Phase 3 Clinical Trials (Type 2 Diabetes)

Pramlintide Placebo

Total Population 1273 420

Completed Trial 968 (76%) 321 (76%)

Withdrew(all reasons)

305 (24%) 99 (24%)

Withdrew(adverse events)

117 (9%) 31 (7%)

First Month Nausea-Related Withdrawals -Type 2 Diabetes

0

0.2

0.4

0.6

0.8

1

1.2

1.4

1.6

137-122 137-123 All studies

PramlintidePlacebo

% withdrawals

Pramlintide Acetate-Safety Review Outline

• Phase 3 Trials





Assisted Hypoglycemia: Definition

• Hypoglycemic event that requires:

– oral carbohydrates

– glucagon

– IV glucose

Assisted Hypoglycemia-Type 1 Diabetes Phase 3 Trials: First Month Incidence

0

2

4

6

8

10

12

14

137-121 137-117 137-112 All studies

PramlintidePlacebo

% patients

Assisted Hypoglycemia-Type 1 Diabetes Phase 3 Trials: End of the First Month to The

End of the Trial Incidence

0

5

10

15

20

25

137-121 137-117 137-112 Allstudies

1stmonth

PramlintidePlacebo

% patients

Change in HbA1c: Study 137-121Type 1 Diabetes

Assisted Hypoglycemia-Type 1 Diabetes Phase 3 Trials: Summary

• Pramlintide therapy is associated with a two fold increase in incidence of assisted hypoglycemia when compared to placebo, during the first month of treatment.


• The difference in incidence of assisted hypoglycemia between pramlintide and placebo groups persists following the first month of treatment albeit to a lower extent.

• This decrease in hypoglycemic events associated with pramlintide takes place in the context of prior nausea-related patient withdrawals and waning drug efficacy.

Assisted Hypoglycemia-Type 2 Diabetes Phase 3 Trials: First Month Incidence

0

0.5

1

1.5

2

2.5

3

137-122 137-123 All studies

PramlintidePlacebo

% patients

Assisted Hypoglycemia-Type 2 Diabetes Phase 3 Trials: End of the First Month to The

End of the Trial Incidence

0

1

2

3

4

5

6

7

8

9

137-122 137-123 All studies 1st month

PramlintidePlacebo

% patients


• Pramlintide therapy is associated with a three fold increase in incidence of assisted hypoglycemia when compared to placebo, during the first month of treatment.


• The difference in incidence of assisted hypoglycemia between pramlintide and placebo groups wanes following the first month of treatment.

• This decrease takes place in the context of prior nausea-related patient withdrawals although to a lower extent than in type 1 diabetes.

Assisted Hypoglycemia: Summary

• The incidence of assisted hypoglycemia was higher during the type 1 and type 2 diabetes trials when compared to controls during both time intervals analyzed.

• Hypoglycemia associated with pramlintide was, however, more common in type 1 diabetes patients.


• Phase 3 Trials





Serious Adverse Events-Definition

• Death

• Life-threatening

• Hospitalization

• Disability

Deaths Possibly Related to Hypoglycemia

• A 48-year-old male with a 12-year history of type 1 diabetes mellitus with a prior history of “diabetes-related seizures“ died during a nocturnal hypoglycemic seizure (pramlintide 30µg QID).

• 35-year-old male with a 6-year history of type 1 diabetes mellitus died in a motor vehicle accident within 24 hours from the beginning of the trial. “Food was present in the stomach at the post-mortem examination, indicating that the subject had eaten lunch prior to the event.” (pramlintide 90 µg TID).


• Phase 3 Trials





Hypoglycemia and Accidents-Type 1 Diabetes

• Motor vehicle accident (MVA)-related events.

• Automobile-related adverse events with no motor vehicle accident reported.

• Other accident/injury-related events (e.g. falls, fractures, lacerations).

MVAs and Automobile-Related Adverse Events-Type 1 Diabetes (All Clinical

Development Program)Pramlintide Placebo

Total Number ofSubjects

2573 904

MVAs(total)

28 (1.8%) 7 (0.66%)

MVAs(with hypoglycemia)

17 (0.66%) 2 (0.22%)

Automobile-relatedHypoglycemic Events(no MVAs)

8 (0.31%) 0

Driving-Related Events Associated With Hypoglycemia -Phase 3 Trials (Type 1

Diabetes)

Treatment Group

Pramlintide Placebo

Total Numberof Subjects

1179 538

Subjects withEvents

18 (1.53%) 2 (0.37%)

Driving-Related Events Associated With Hypoglycemia - Type 1 Diabetes:

Conclusion

• Pramlintide use in addition to insulin is associated with a four fold increase in driving-related events in type 1 diabetes patients.

Other Accidents and Injuries-Type 1 Diabetes (All Clinical Development Program)

Pramlintide Placebo

Total Number of Subjects 2573 904

All Subjects with Events 197 (7.65%) 53 (5.86%)

Subjects with Events andHypoglycemia

10 (0.39%) 2 (0.22)

Other Accidents and Injuries-Phase 3 Trials (Type 1 Diabetes)

Treatment Group

Pramlintide Placebo

Total Numberof Subjects

1179 538

Subjects withEvents(Number and %)

9 (0.76%) 1 (0.18%)

Other Accidents and Injuries- Type 1 Diabetes: Conclusion

• Pramlintide use in addition to insulin is associated with a four fold increase in non-MVA injuries in type 1 diabetes patients.

Severe Hypoglycemia:Labeling Question

• Do we know how to initiate safely pramlintide treatment and avoid the risk of first month hypoglycemia in both patients with type 1 and type 2 diabetes?


Sponsor’s suggestions:“Initiate treatment with 30 µg or 60 µg of pramlintide per dose in type 1 diabetics and 120 µg per dose in type 2 diabetics”.

FDA comments:

All above doses have been shown to be associated with a two fold increased risk of assisted hypoglycemia during the phase 3 trials.


Sponsor’s suggestions:“In clinical practice it would be prudent to reduce the patient’s insulin dose, particularly the short-acting insulin administered preprandially by 10-20% at the time of initiation of pramlintide therapy.”

FDA comments:

While such an approach seems prudent it has not been tested in a clinical trial and its potential usefulness remains unknown.

Accidents Associated With Hypoglycemia-Labeling Question

• How can one prevent the four fold risk of driving-related events and the four fold risk of non-MVA injuries associated with hypoglycemia observed in the type 1 diabetes trials?

Time of Driving-Related Events vs HbA1c

4

5

6

7

8

9

10

11

12

0 2 4 6 8 10 12

Months

Hg

bA

1c (

%)

= pramlintide= placebo

SummaryPramlintide therapy results in a small but statistically significant reduction in HbA1c.

This reduction is associated with a two fold increase of severe hypoglycemia during the first month of treatment.

In addition, a four fold increase in hypoglycemia- associated MVAs and non-MVA trauma, was observed in patients with type 1 diabetes.

Date post:	18-Dec-2015
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Pramlintide Acetate Safety Review Dragos Roman MD Center for Drug Evaluation and Research.

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